Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data from secondry source

Data source

Referenceopen allclose all

Reference Type:
other: Secondary source
Title:
Developmental toxicity study of test chemical
Author:
U. S. Environmental Protection Agency (EPA) Office of Pollution Prevention and Toxic Substances (OPPTS)
Year:
2010
Bibliographic source:
U.S. Environmental Protection Agency Hazard Characterization Document. Published 2010
Reference Type:
other: Secondary source
Title:
Developmental toxicity study of test chemical
Author:
Human and Environmental Risk Assessment
Year:
2005
Bibliographic source:
Human and Environmental Risk Assessment, 2005
Reference Type:
other: secondary source
Title:
Developmental toxicity study of test chemical
Author:
OECD HPV Chemical Program
Year:
2006
Bibliographic source:
SIDS Dossier, 2006

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Developmental toxicity study of test material was performed on female CD rats.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-Propanaminium, 3-amino-N-(carboxymethyl)-N,N-dimethyl-, N-coco acyl derivs., hydroxides, inner salts
EC Number:
263-058-8
EC Name:
1-Propanaminium, 3-amino-N-(carboxymethyl)-N,N-dimethyl-, N-coco acyl derivs., hydroxides, inner salts
Cas Number:
61789-40-0
Molecular formula:
C19H38N2O3
IUPAC Name:
1-Propanaminium, 3-amino-N-(carboxymethyl)-N,N-dimethyl-, N-coco acyl derivs., hydroxides, inner salts
Details on test material:
IUPAC name:1-Propanaminium, 3-amino-N-(carboxymethyl)-N,N-dimethyl-, N-coco acyl derivs., hydroxides, inner salts
Mol. formula:C19H38N2O3
Mol. wt.:342.52 g·mol−1
Smile:CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC([O-])=OCCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC(=O)[O-]
InChI:[O-]C(=O)C[N+](CCCNC(=O)CCCCCCCCCCC)(C)C1S/C19H38N2O3/c1-4-5-6-7-8-9-10-11-12-14-18(22)20-15-13-16-21(2,3)17-19(23)24/h4-17H2,1-3H3,(H-,20,22,23,24)
Substance type: Organic

Test animals

Species:
rat
Strain:
other: CD
Details on test animals or test system and environmental conditions:
Age at day 0 of pregnancy: 8 - 9 weeks- Body weight at day 0 of pregnancy: 205 - 254 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
(aqua ad iniectabilia)
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS:Test material soluble in water (aqua ad iniectabilia)

DIET PREPARATION
- Rate of preparation of diet (frequency):- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0, 330, 990 or3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively)
- Amount of vehicle (if gavage):10ml /kg bw
- Lot/batch no. (if required)
:- Purity:
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: during the dark period.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- Any other deviations from standard protocol:
Duration of treatment / exposure:
15 days (from day 5 - 19 of pregnancy)
Frequency of treatment:
Daily
Duration of test:
20 days
Doses / concentrations
Remarks:
0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively)
No. of animals per sex per dose:
Total:
1000 mg/kg : 25 female
95 mg/kg:25 female
286 mg/kg:25 female
950 mg/kg:25 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data available

Examinations

Maternal examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes
DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: daily
BODY WEIGHT: Yes, Time schedule for examinations: daily
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes daily Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Compound intake calculated as time
-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
Postmortem examinations (Parent Animal)
SACRIFICE : on days 20
GROSS NECROPSY: yes
HISTOPATHOLOGY / ORGAN WEIGHTS : yes
Indices:
No data available
Historical control data:
No data available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
At 3300 mg/kg bw dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
One dam at 3300 mg/kg day died on gestation day 15
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
>= 990 mg/kg bw dose group reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%). At 3300 mg/kg bw dose group reduced body weight (up to 17 % below control) and decreased body weight change were observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
>= 990 mg/kg bw dose group reduced food consumption (up to 12 % gestation days 8, 10, 19)and at 3300 mg/kg bw dose group up to 65% each day
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In 3300 mg/kg bw dose group reduced gravid uterus weight by 22% (caused by lowered fetal weights)
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At 990 mg/kg bw dose group 4/20: ulcers, thickened mucosa and in 3300 mg/kg bw dose group 20/21: thickened mucosa, greyish discoloured in 2/21; ulcers (also in the prematurely deceased dam) were observed.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in the 3300 mg/kg bw dose group.
Total litter losses by resorption:
not specified
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
The number of early, late and total resorptions was increased in the 3300 mg/kg bw group.
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not specified

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
95 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
gross pathology
mortality
organ weights and organ / body weight ratios
pre and post implantation loss
total litter losses by resorption
Remarks on result:
other: No toxic effects observed at given dose group

Maternal abnormalities

Abnormalities:
not specified
Localisation:
not specified

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
a statistically significant reduction in fetal weights as compared to the control was observed At 3300 mg/kg bw dose group
Description (incidence and severity):
a statistically significant reduction in number of viable fetuses as compared to the control was observed At 3300 mg/kg bw dose group
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
No external malformations and no external variations were seen in controls or in dosed groups.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No skeletal were seen in controls or in dosed groups.
Visceral malformations:
no effects observed
Description (incidence and severity):
No soft tissue malformations were seen in controls or in dosed groups.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw). The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 950 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations
Remarks on result:
other: No developmental toxic effects observed

Fetal abnormalities

Abnormalities:
not specified
Localisation:
other: not specified

Overall developmental toxicity

Developmental effects observed:
not specified
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean foetal body weight were considered to be secondary to maternal toxicity when female CD were treated with test chemical orally from day 5 - 19 of pregnancy.
Executive summary:

The prenatal developmental toxicity study following OECD guideline 414 was performed on female CD rats. Test material was soluble in water (aqua ad iniectabilia). Dose concentration were prepared at 0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively) and administered in a dose volume of 10 ml/kg bw from day 5 to 19 of pregnancy once daily via gavage. 25 female rats /dose group were treated and 20 pregnant animals were evaluated. 20 rats (0, 330, 990 mg/kg bw group) and 21 rats (3300 mg/kg bw group) were evaluated for maternal toxicity. 1 male and 1 female were placed in one cage during the dark period. Mating was repeated until vaginal smear showed presence of sperm. All animals were observed for clinical signs, Body weight and food consumption daily. Also number of fetuses alive, Weight of fetuses, sex distribution of fetuses, skeletal anomalies (50 %) and soft tissue anomalies (50 %) were noted. One dam at 3300 mg/kg day died on gestation day 15 and in same dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility was noted. At≥990 mg/kg bw dose group, reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%) and reduced food consumption (up to 12 % gestation days 8, 10, 19), 4/20: ulcers, thickened mucosa were observed. At 3300 mg/kg bw dose group, reduced body weight (up to 17 % below control) and decreased body weight change, reduced food consumption up to 65% each day, reduced gravid uterus weight by 22% (caused by lowered fetal weights) and 20/21: thickened mucosa, greyish discolored in 2/21; ulcers (also in the prematurely deceased dam) were observed. The number of early, late and total resorptions was increased in the 3300 mg/kg bw group. Moreover the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in this dose group. A statistically significant reduction in fetal weights and number of viable fetuses as compared to the control was observed. At 3300 mg/kg bw dose group. No external, skeletal or soft tissue malformations and no external variations were seen in controls or in dosed groups. The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw) in the test group respectively. The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw). Hence, the NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for reproductive and developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean fetal body weight were considered to be secondary to maternal toxicity when female CD rats were treated with test chemical orally from day 5 - 19 of pregnancy.